Harnessing the immune system to target cellular senescence

Deciduous Therapeutics aims for clinical trials of immune-activating senotherapeutic by 2023, with metabolic disease and fibrosis among potential indications.

Californian start-up Deciduous Therapeutics has emerged from stealth mode following the publication of a new paper that reveals the science behind its approach to eliminating senescent cells. Deciduous is working on therapeutics designed to temporarily activate immune cells – known as invariant Natural Killer T (iNKT) cells – that eliminate senescent cells and offer a potential alternative to senolytic therapies.

The paper, published yesterday by scientists at UC San Francisco, found that iNKT cells eliminate senescent cells but become less active with age and other factors that contribute to chronic disease. The UCSF researchers used lipid antigens to activate iNKT cells in mice, which reduced senescent cells and improved blood glucose levels in diet-induced obese mice. In a second study, the researchers showed that the same approach in mice with lung fibrosis also reduced senescent cells and fibrosis, accompanied by improved survival rates.

Longevity.Technology: The world of senotherapeutics encompasses a range of different methods when it comes to addressing the problem of cellular senescence. With its focus on immune mechanisms, Deciduous is taking a very interesting approach, so we caught up with CEO and co-founder Robin Mansukhani to learn more.

As we age, accumulation of senescent cells in our bodies induces inflammation and promotes extracellular matrix remodelling. This accumulation is thought to be a key driving force behind many age-related diseases, particularly metabolic and fibrotic conditions. Targeting and removing senescent cells is a key focus of senotherapeutic research and development.

Deciduous’ roots

In late 2018, The Longevity Fund’s Laura Deming and UCSF professor Anil Bhushan approached Mansukhani with the idea behind Deciduous.

“I’d been following the story of senescence for a couple years, so I was very familiar with it,” he says. “The current approaches in the field had really interesting data, but given the heterogeneic profile of a senescent cell, I was concerned about specificity and therefore potential off-target effects. Then Anil told me that he was working on understanding the immune process that naturally clears senescent cells, and that they had a handle on what it was. So the founding premise of the company was that there was an immune target here, but there was a lot of work to be done.”

The proposed approach made a lot of sense to Mansukhani.
“I just felt that if you want to do this and win in the long term, you need to follow the immune system,” he says. “How does this normally happen? What is going wrong? And then, if you can figure out what’s going wrong, can you treat it? Can you therapeutically modulate it back to where it should be?”

Deciduous Therapeutics is based at the MBC Biolabs incubator in San Francisco.

The company has since focused on validating the immune mechanism target, learning if it could be activated therapeutically to clear senescent cells, and whether novel compounds could be developed to create the effect in humans.

“And I think the most important question was, does it actually achieve relevant therapeutic endpoints across the spectrum?” says Mansukhani. “If you can remove senescent cells, but it doesn’t move the needle on disease, then it doesn’t matter. And so, the most convincing data shown in the paper, is that this approach can treat both metabolic disease and lung fibrosis with single, intermittent low-dose treatments.”

All about iNKT

After conducting single cell RNA sequencing of senescent cells, an immune cell footprint emerged, which was the iNKT cell.

“And so the question was, what’s happening here between these two cells – why does iNKT talk to this senescent cell, why does it remove it?” says Mansukhani, who likens the process to that of tumour immunology. “With tumours, the immune cell recognises the damage-associated molecular patterns being given off by the tumour cell and they basically get attracted to each other. So it’s the same concept, but for senescence cells and a different kind of immune cell – they have this natural connection.”

The key issue is that the iNKT cell that kills the senescent cell gets slow as we age, and it gets even slower in the presence of disease.

“And so the idea was, can we just nudge them back up to where they need to be in order to actually clear out these senescent cells?” says Mansukhani. “There’s a natural immune function here, our data suggests it’s the iNKT cell doing this, but it’s just slow. And so we therapeutically make it quicker. But we only make it quicker for a short amount of time, because if you have chronic immune activation, that also can be deleterious to your goals.”

The iNKT cells have two attributes that make them an especially appealing drug target. First, they all have the same receptor, which does not appear on any other cell in the body, so they can be primed without also activating other types of immune cells. Second, they operate within a natural negative feedback loop that returns them to a dormant state after a period of activity.

Clinical trials in 2023

Building on the work conducted on mice as reported in the new paper, Deciduous has gone on to develop an estate of novel human therapeutics – both small molecules and antibodies.

“We’ve taken the basic idea from the paper and translated that into novel molecules that would function on the human immune system – we optimise it for human immune cells,” says Mansukhani. “We’ve then replicated a lot of the data that’s shown in the paper, and now forging ahead into additional models.”

As things can change rapidly in the world of R&D, Mansukhani feels that, while the current data points towards lead indications of idiopathic pulmonary fibrosis (IPF) and metabolic disease, the mechanism provides long term optionality.

“By the time we get to the clinical stage, we should have several more in vivo proof of concepts across multiple disease classes,” he says. “In the meantime, we have lead candidates, which we’re now pushing through development, with the goal of initiating clinical trials in 2023.”

Having raised around $6.5 million in pre-seed and seed funding, Deciduous has just started conversations with investors to raise a Series A funding round that should bring the company through those first human trials.

Intrigued by the exciting and developing senotherapeutics field? Our market intelligence report on senotherapeutics is now available – order your copy here and watch out for more senotherapeutics-related articles coming soon.

Images courtesy of Deciduous Therapeutics